Gonadotropin-releasing hormone receptor antagonists and methods relating thereto

ABSTRACT

GnRH receptor antagonists are disclosed which have utility in the treatment of a variety of sex-hormone related conditions in both men and women. The compounds of this invention have the structure: 
                 
 
wherein A, R 1 , R 2 , R 3a , R 3b , R 4 , R 5 , R 6 , R 7  and n are as defined herein, including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof. Also disclosed are compositions containing a compound of this invention in combination with a pharmaceutically acceptable carrier, as well as methods relating to the use thereof for antagonizing gonadotropin-releasing hormone in a subject in need thereof.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional PatentApplication No. 60/309,937, filed Aug. 2, 2001, which application isincorporated herein by reference in its entirety.

STATEMENT OF GOVERNMENT INTEREST

Partial funding of the work described herein was provided by the U.S.Government under Grant No. R43-HD38625 provided by the NationalInstitute of Health. The U.S. Government may have certain rights in thisinvention.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates generally to gonadotropin-releasing hormone(GnRH) receptor antagonists, and to methods of treating disorders byadministration of such antagonists to a warm-blooded animal in needthereof.

2. Description of the Related Art

Gonadotropin-releasing hormone (GnRH), also known as luteinizinghormone-releasing hormone (LHRH), is a decapeptide(pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH₂) that plays an importantrole in human reproduction. GnRH is released from the hypothalamus andacts on the pituitary gland to stimulate the biosynthesis and release ofluteinizing hormone (LH) and follicle-stimulating hormone (FSH). LHreleased from the pituitary gland is responsible for the regulation ofgonadal steroid production in both males and females, while FSHregulates spermatogenesis in males and follicular development infemales.

Due to its biological importance, synthetic antagonists and agonists toGnRH have been the focus of considerable attention, particularly in thecontext of prostate cancer, breast cancer, endometriosis, uterineIciomyoma, and precocious puberty. For example, peptidic GNRH agonists,such as leuprorelin (pGlu-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt), havebeen used to treat such conditions. Such agonists appear to function bybinding to the GnRH receptor in the pituitary gonadotropins, therebyinducing the synthesis and release of gonadotropins. Chronicadministration of GnRH agonists depletes gonadotropins and subsequentlydown-regulates the receptor, resulting in suppression of steroidalhormones after some period of time (e.g., on the order of 2-3 weeksfollowing initiation of chronic administration).

In contrast, GnRH antagonists are believed to suppress gonadotropinsfrom the onset, and thus have received the most attention over the pasttwo decades. To date, some of the primary obstacles to the clinical useof such antagonists have been their relatively low bioavailability andadverse side effects caused by histamine release. However, severalpeptidic antagonists with low histamine release properties have beenreported, although they still must be delivered via sustained deliveryroutes (such as subcutaneous injection or intranasal spray) due tolimited bioavailability.

In view of the limitations associated with peptidic GnRH antagonists, anumber of nonpeptidic compounds have been proposed. For example, Cho etal. (J. Med. Chem. 41:4190-4195, 1998) disclosesthieno[2,3-b]pyridin-4-ones for use as GnRH receptor antagonists; U.S.Pat. Nos. 5,780,437 and 5,849,764 teach substituted indoles as GnRHreceptor antagonists (as do published PCTs WO 97/21704, 98/55479,98/55470, 98/55116, 98/55119, 97/21707, 97/21703 and 97/21435);published PCT WO 96/38438 discloses tricyclic diazepines as GnRHreceptor antagonists; published PCTs WO97/14682, 97/14697 and 99/09033disclose quinoline and thienopyridine derivatives as GnRH antagonists;published PCTs WO 97/44037, 97/44041, 97/44321 and 97/44339 teachsubstituted quinolin-2-ones as GnRH receptor antagonists; and publishedPCT WO 99/33831 discloses certain phenyl-substituted fusednitrogen-containing bicyclic compounds as GnRH receptor antagonists.

While significant strides have been made in this field, there remains aneed in the art for effective small molecule GnRH receptor antagonists.There is also a need for pharmaceutical compositions containing suchGnRH receptor antagonists, as well as methods relating to the usethereof to treat, for example, sex-hormone related conditions. Thepresent invention fulfills these needs, and provides other relatedadvantages.

BRIEF SUMMARY OF THE INVENTION

In brief, this invention is generally directed to gonadotropin-releasinghormone (GnRH) receptor antagonists, as well as to methods for theirpreparation and use, and to pharmaceutical compositions containing thesame. More specifically, the GnRH receptor antagonists of this inventionare compounds having the following general structure (I):

including stereoisomers, prodrugs and pharmaceutically acceptable saltsthereof, wherein A, R₁, R₂, R_(3a), R_(3b), R₄, R₅, R₆, R₇ and n are asdefined below.

The GnRH receptor antagonists of this invention have utility over a widerange of therapeutic applications, and may be used to treat a variety ofsex-hormone related conditions in both men and women, as well as amammal in general (also referred to herein as a “subject”). For example,such conditions include endometriosis, uterine fibroids, polycysticovarian disease, hirsutism, precocious puberty, gonadalsteroid-dependent neoplasia such as cancers of the prostate, breast andovary, gonadotrophe pituitary adenomas, sleep apnea, irritable bowelsyndrome, premenstrual syndrome, benign prostatic hypertrophy,contraception and infertility (e.g., assisted reproductive therapy suchas in vitro fertilization). The compounds of this invention are alsouseful as an adjunct to treatment of growth hormone deficiency and shortstature, and for the treatment of systemic lupus erythematosis. Thecompounds are also useful in combination with androgens, estrogens,progesterones, and antiestrogens and antiprogestogens for the treatmentof endometriosis, fibroids, and in contraception, as well as incombination with an angiotensin-converting enzyme inhibitor, anangiotensin II-receptor antagonist, or a renin inhibitor for thetreatment of uterine fibroids. In addition, the compounds may be used incombination with bisphosphonates and other agents for the treatmentand/or prevention of disturbances of calcium, phosphate and bonemetabolism, and in combination with estrogens, progesterones and/orandrogens for the prevention or treatment of bone loss or hypogonadalsymptoms such as hot flashes during therapy with a GnRH antagonist.

The methods of this invention include administering an effective amountof a GnRH receptor antagonist, preferably in the form of apharmaceutical composition, to a mammal in need thereof. Thus, in stilla further embodiment, pharmaceutical compositions are disclosedcontaining one or more GnRH receptor antagonists of this invention incombination with a pharmaceutically acceptable carrier and/or diluent.

These and other aspects of the invention will be apparent upon referenceto the following detailed description. To this end, various referencesare set forth herein which describe in more detail certain backgroundinformation, procedures, compounds and/or compositions, and are eachhereby incorporated by reference in their entirety.

DETAILED DESCRIPTION OF THE INVENTION

As mentioned above, the present invention is directed generally tocompounds useful as gonadotropin-releasing hormone (GnRH) receptorantagonists. The compounds of this invention have the followingstructure (I):

including stereoisomers, prodrugs and pharmaceutically acceptable saltsthereof,wherein:

A is O or a bond;

n is 1, 2, 3 or 4;

R₁ and R₂ are the same or different and independently hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl,substituted heterocyclealkyl, —C(R₈)(═NR₉) or —C(NR₁₀R₁₁)(═NR₉);

or R₁ and R₂ taken together with the nitrogen atom to which they areattached form a heterocycle or a substituted heterocycle;

R_(3a) and R_(3b) are the same or different and, at each occurrence,independently hydrogen, alkyl, substituted alkyl, alkoxy, alkylthio,alkylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl,heterocycle, substituted heterocycle, heterocyclealkyl, substitutedheterocyclealkyl, —COOR₁₂ or —CONR₁₀R₁₁;

or R_(3a) and R_(3b) taken together with the carbon atom to which theyare attached form a homocycle, substituted homocycle, heterocycle orsubstituted heterocycle;

or R_(3a) and the carbon to which it is attached taken together with R₁and the nitrogen to which it is attached form a heterocycle orsubstituted heterocycle;

R₄ is hydrogen, alkyl or substituted alkyl;

R₅ is arylalkyl, substituted arylalkyl, heteroarylalkyl or substitutedheteroarylalkyl;

R₆ is aryl, substituted aryl, heteroaryl or substituted heteroaryl;

R₇ is hydrogen, alkyl or substituted alkyl;

R₈, R₉, R₁₀ and R₁₁ are the same or different and, at each occurrence,independently hydrogen, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, heterocycle, substitutedheterocycle, heterocyclealkyl or substituted heterocyclealkyl; and

R₁₂ is hydrogen, alkyl or substituted alkyl.

As used herein, the above terms have the following meaning:

“Alkyl” means a straight chain or branched, noncyclic or cyclic,unsaturated or saturated aliphatic hydrocarbon containing from 1 to 10carbon atoms, while the term “lower alkyl” has the same meaning as alkylbut contains from 1 to 6 carbon atoms. The term “higher alkyl” has thesame meaning as alkyl but contains from 2 to 10 carbon atoms.Representative saturated straight chain alkyls include methyl, ethyl,n-propyl, n-butyl, n-pentyl, n-hexyl, and the like; while saturatedbranched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl,isopentyl, and the like. Representative saturated cyclic alkyls includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; whileunsaturated cyclic alkyls include cyclopentenyl and cyclohexenyl, andthe like. Cyclic alkyls are also referred to herein as a “homocycles” or“homocyclic rings.” Unsaturated alkyls contain at least one double ortriple bond between adjacent carbon atoms (referred to as an “alkenyl”or “alkynyl,” respectively). Representative straight chain and branchedalkenyls include ethylenyl, propylenyl, 1-butenyl, 2-butenyl,isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl,2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, and the like; whilerepresentative straight chain and branched alkynyls include acetylenyl,propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl,3-methyl-1-butynyl, and the like.

“Aryl” means an aromatic carbocyclic moiety such as phenyl or naphthyl.

“Arylalkyl” means an alkyl having at least one alkyl hydrogen atomsreplaced with an aryl moiety, such as benzyl, —(CH₂)₂phenyl,—(CH₂)₃phenyl, —CH(phenyl)₂, and the like.

“Heteroaryl” means an aromatic heterocycle ring of 5- to 10 members andhaving at least one heteroatom selected from nitrogen, oxygen andsulfur, and containing at least 1 carbon atom, including both mono- andbicyclic ring systems. Representative heteroaryls are furyl,benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl,isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl,isooxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl,thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl,pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl.

“Heteroarylalkyl” means an alkyl having at least one alkyl hydrogen atomreplaced with a heteroaryl moiety, such as —CH₂pyridinyl,—CH₂pyrimidinyl, and the like.

“Heterocycle” (also referred to herein as a “heterocyclic ring”) means a4- to 7-membered monocyclic, or 7- to 10-membered bicyclic, heterocyclicring which is either saturated, unsaturated, or aromatic, and whichcontains from 1 to 4 heteroatoms independently selected from nitrogen,oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms maybe optionally oxidized, and the nitrogen heteroatom may be optionallyquaternized, including bicyclic rings in which any of the aboveheterocycles are fused to a benzene ring. The heterocycle may beattached via any heteroatom or carbon atom. Heterocycles includeheteroaryls as defined above. Thus, in addition to the heteroarylslisted above, heterocycles also include morpholinyl, pyrrolidinonyl,pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl,oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl,tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl,tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, andthe like.

“Heterocyclealkyl” means an alkyl having at least one alkyl hydrogenatom replaced with a heterocycle, such as —CH₂morpholinyl, and the like.

“Homocycle” (also referred to herein as “homocyclic ring”) means asaturated or unsaturated (but not aromatic) carbocyclic ring containingfrom 3-7 carbon atoms, such as cyclopropane, cyclobutane, cyclopentane,cyclohexane, cycloheptane, cyclohexene, and the like.

The term “substituted” as used herein means any of the above groups(i.e., alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, homocycle,heterocycle and/or heterocyclealkyl) wherein at least one hydrogen atomis replaced with a substituent. In the case of an oxo substituent (“═O”)two hydrogen atoms are replaced. When substituted one or more of theabove groups are substituted, “substituents” within the context of thisinvention include halogen, hydroxy, oxo, cyano, nitro, amino,alkylamino, dialkylamino, alkyl, alkoxy, alkylthio, haloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocycle andheterocyclealkyl, as well as —NR_(a)R_(b), —NR_(a)C(═O)R_(b),—NR_(a)C(═O)NR_(a)NR_(b), —NR_(a)C(═O)OR_(b) —NR_(a)SO₂R_(b),—C(═O)R_(a), —C(═O)OR_(a), —C(═O)NR_(a)R_(b), —OC(═O)NR_(a)R_(b),—OR_(a), —SR_(a), —SOR_(a), —S(═O)₂R_(a), —OS(═O)₂R_(a) and—S(═O)₂OR_(a). In addition, the above substituents may be furthersubstituted with one or more of the above substituents, such that thesubstituent substituted alky, substituted aryl, substituted arylalkyl,substituted heterocycle or substituted heterocyclealkyl. R_(a) and R_(b)in this context may be the same or different and independently hydrogen,alkyl, haloalkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, heterocycle, substituted heterocycle,heterocyclealkyl or substituted heterocyclealkyl.

“Halogen” means fluoro, chloro, bromo and iodo.

“Haloalkyl” means an alkyl having at least one hydrogen atom replacedwith halogen, such as trifluoromethyl and the like.

“Alkoxy” means an alkyl moiety attached through an oxygen bridge (i.e.,—O-alkyl) such as methoxy, ethoxy, and the like.

“Alkylthio” means an alkyl moiety attached through a sulfur bridge(i.e., —S-alkyl) such as methylthio, ethylthio, and the like.

“Alkylsulfonyl” means an alkyl moiety attached through a sulfonyl bridge(i.e., —SO₂-alkyl) such as methylsulfonyl, ethylsulfonyl, and the like.

“Alkylamino” and “dialkylamino” mean one or two alkyl moiety attachedthrough a nitrogen bridge (i.e., —N-alkyl) such as methylamino,ethylamino, dimethylamino, diethylamino, and the like.

With regard to the “R₁R₂N(CR_(3a)R_(3b))_(n)—” moiety of structure (I),n may be 1, 2, 3 or 4. Accordingly, this moiety may be represented bythe following structure (i) when n is 1, (ii) when n is 2, structure(iii) when n is 3, and structure (iv) when n is 4:

wherein each occurrence of R_(3a) and R_(3b) above may be the same ordifferent, and are as defined above. For example, when each occurrenceof R_(3a) and R_(3b) in structures (i), (ii) (iii) and (iv) is hydrogen,the “R₁R₂N(CR_(3a)R_(3b))_(n)—” moiety has the structure R₁R₂N(CH₂)—,R₁R₂N(CH₂)₂—, R₁R₂N(CH₂)₃— and R₁R₂N(CH₂)₄—, respectively.

The compounds of the present invention may be prepared by known organicsynthesis techniques, including the methods described in more detail inthe Examples. However in general, the compounds of structure (I) abovemay be made by the following Reaction Schemes. All substituents in thefollowing Reaction Schemes are as defined above unless indicatedotherwise.

Ketone or aldehyde 1 and an amine are dissolved neat or with a cosolventin an alkylorthoformate at a temperature of 0-50° C. for 12 to 36 hoursto give enamine 2. Compound 2 in the presence of a substituted dioxinonein a protic solvent at elevated or reflux temperature for 1-12 hoursgives product 3. Alternatively, compound 1 may be alkylated with asubstituted acyl halide in the presence of a base such as sodium hydrideor potassium t-butoxide in a solvent such as THF or dioxane for 1-24hours at 0 to 50° C. to give 4. 4 in the presence of a substituted alkylorthoester in a protic solvent at reflux for 1-24 hours gives 5. 5 and aprimary amine, neat or in an inert solvent such as DMF or DMSO, areheated at an elevated temperature or at reflux temperature for 1-24hours to give compound 3. (T. T. Tidweil, J. Org. Chem., 1998, 63, 8636)

Compound 1 in the presence of a substituted aminocrotonate 6 is heatedto 75-150° C. in a solvent such as toluene to give aminocrotonate 7which cyclizes upon heating to give 8. (T. Kametani, J. Heterocycl.Chem., 1977, 477)

Meldrum's acid 9 and a substituted acetyl halide in the presence of abase such as TEA or pyridine in a solvent such as THF or dichloromethaneis stirred for 1-24 hours at a temperature of 20-75° C. The reaction mixis evaporated and following a quick workup, the residue is refluxed inan alcohol to give β-keto ester 10. Compound 10 in the presence oftriazine or DMFDMA followed by ammonium acetate gives compound 11. Useof a primary amine in place of ammonium acetate gives 11 with asubstitution on the nitrogen. (M. Balogh, J. Heterocycl. Chem., 1980,359; R. Kiyama, Chem. Pharm. Bull., 1995,43,450)

Pyridone 12 is alkylated with an alkyl halide in the presence of a basesuch as sodium hydride or potassium carbonate in a solvent such as DMFor acetonitrile at 0 to 50° C. for 1-24 hours to give alkylated compound3.

Pyridone 13 may be halogenated using bromine/acetic acid, ICl inchloroform, or NIS or NBS in a solvent such as chloroform at 0-50° C.for 1-24 hours to give 14. Compound 14 and an appropriate boronic acidundergoes a Suzuki coupling to give compound 3.

Pyridone ester 15 and a Grignard reagent at −78° C. in ether or THF for¼ to 4 hours, or using DIBAL-H at −78° C. for approximately 2 hours inTHF or ether gives 16. Reductive amination of 16 with a primary orsecondary amine using a reagent such as sodium cyanoborohydride orsodium triacetoxyborohydride at 0-50° C. in an aprotic solvent such asmethylene chloride for 1-24 hours gives 17. Treatment of 16 with anappropriate phosphonum salt and a base such as LDA or HMDS gives an enolthat is hydrolized by treatment with an aqueous acid such as HCl to give18. Reductive amination with an appropriate amine gives compound 19.

Compounds of structure (I) may generally be referred to as substituted1H-pyridin-4-one compounds, representative compounds of which includethe following:

3-(2-Amino-2-phenyl-ethyl)-1-(2,6-difluoro-benzyl)-2,6-dimethyl-5-(2-fluoro-3-methoxy-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2,6-dichloro-benzyl)-2,6-dimethyl-5-(2-fluoro-3-methoxy-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2-fluoro-6-chloro-benzyl)-2,6-dimethyl-5-(2-fluoro-3-methoxy-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-2,6-dimethyl-5-(2-fluoro-3-methoxy-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2-fluoro-6-methylsulfonyl-benzyl)-2,6-dimethyl-5-(2-fluoro-3-methoxy-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2-fluoro-benzyl)-2,6-dimethyl-5-(2-fluoro-3-methoxy-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2-chloro-benzyl)-2,6-dimethyl-5-(2-fluoro-3-methoxy-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2-trifluoromethyl-benzyl)-2,6-dimethyl-5-(2-fluoro-3-methoxy-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2-methylsulfonyl-benzyl)-2,6-dimethyl-5-(2-fluoro-3-methoxy-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2,6-difluoro-benzyl)-2,6-dimethyl-5-(2-fluoro-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2,6-dichloro-benzyl)-2,6-dimethyl-5-(2-fluoro-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2-fluoro-6-chloro-benzyl)-2,6-dimethyl-5-(2-fluoro-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-2,6-dimethyl-5-(2-fluoro-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2-fluoro-6-methylsulfonyl-benzyl)-2,6-dimethyl-5-(2-fluoro-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2-fluoro-benzyl)-2,6-dimethyl-5-(2-fluoro-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2-chloro-benzyl)-2,6-dimethyl-5-(2-fluoro-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2-trifluoromethyl-benzyl)-2,6-dimethyl-5-(2-fluoro-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2-methylsulfonyl-benzyl)-2,6-dimethyl-5-(2-fluoro-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2,6-difluoro-benzyl)-2,6-dimethyl-5-(2-chloro-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2,6-dichloro-benzyl)-2,6-dimethyl-5-(2-chloro-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2-fluoro-6-chloro-benzyl)-2,6-dimethyl-5-(2-chloro-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-2,6-dimethyl-5-(2-chloro-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2-fluoro-6-methylsulfonyl-benzyl)-2,6-dimethyl-5-(2-chloro-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2-fluoro-benzyl)-2,6-dimethyl-5-(2-chloro-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2-chloro-benzyl)-2,6-dimethyl-5-(2-chloro-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2-trifluoromethyl-benzyl)-2,6-dimethyl-5-(2-chloro-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2-methylsulfonyl-benzyl)-2,6-dimethyl-5-(2-chloro-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2,6-difluoro-benzyl)-2,6-dimethyl-5-(3-methoxy-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2,6-dichloro-benzyl)-2,6-dimethyl-5-(3-methoxy-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2-fluoro-6-chloro-benzyl)-2,6-dimethyl-5-(3-methoxy-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-2,6-dimethyl-5-(3-methoxy-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2-fluoro-6-methylsulfonyl-benzyl)-2,6-dimethyl-5-(3-methoxy-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2-fluoro-benzyl)-2,6-dimethyl-5-(3-methoxy-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2-chloro-benzyl)-2,6-dimethyl-5-(3-methoxy-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2-trifluoromethyl-benzyl)-2,6-dimethyl-5-(3-methoxy-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2-methylsulfonyl-benzyl)-2,6-dimethyl-5-(3-methoxy-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2,6-difluoro-benzyl)-2,6-dimethyl-5-(2-chloro-3-methoxy-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2,6-dichloro-benzyl)-2,6-dimethyl-5-(2-chloro-3-methoxy-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2-fluoro-6-chloro-benzyl)-2,6-dimethyl-5-(2-chloro-3-methoxy-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-2,6-diinethyl-5-(2-chloro-3-methoxy-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2-fluoro-6-methylsulfonyl-benzyl)-2,6-dimethyl-5-(2-chloro-3-methoxy-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2-fluoro-benzyl)-2,6-dimethyl-5-(2-chloro-3-methoxy-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2-chloro-benzyl)-2,6-dimethyl-5-(2-chloro-3-methoxy-phenyl)-1H-pyridin-4-one;

3-(2-Amino-2-phenyl-ethyl)-1-(2-trifluoromethyl-benzyl)-2,6-dimethyl-5-(2-chloro-3-methoxy-phenyl)-1H-pyridin-4-one;and

3-(2-Amino-2-phenyl-ethyl)-1-(2-methylsulfonyl-benzyl)-2,6-dimethyl-5-(2-chloro-3-methoxy-phenyl)-1H-pyridin-4-one.

In addition, representative compounds of the present invention alsoinclude those compounds where the primary amine of the above namedcompounds is substituted with a substituted alkyl group or a cycloalkylgroup. As described in the examples, one method of alkylating amines andamides is by reductive alkylation. There are many alternative methodswell known in the chemical arts for accomplishing the reductivealkylation procedure, and there are many alternative alkylation methods.When an aldehyde, ketone, carboxylic acid, or acid chloride is treatedwith a primary or secondary amine in the presence of a reducing agentreductive alkylation may take place. Suitable reducing agents include(but are not limited to) sodium borohydride, sodiumtriacetoxyborohydride, sodium cyanoborohydride, hydrogen gas and ahydrogenation catalyst, zinc and hydrochloric acid, iron pentacarbonyland alcoholic potassium hydroxide, formic acid, pyridine borohydride.Amines and amides may also be alkylated by the reaction of formaldehydeand a Mannich base or by the nucleophilic displacement of an alkylhalide or other leaving groups. As an example, the Mitsunobu reactionallows the alkylation of amines with primary or secondary alcohols andcarboxylic acids by activation of the hydroxyl group withtriphenylphosphine to form the leaving group triphenylphoshine oxide.Other commonly used alkylation methods are described in March, AdvancedOrganic Chemistry, 4th Ed., pp 1276-1277 (1992).

The compounds of the present invention may generally be utilized as thefree acid or free base. Alternatively, the compounds of this inventionmay be used in the form of acid or base addition salts. Acid additionsalts of the free amino compounds of the present invention may beprepared by methods well known in the art, and may be formed fromorganic and inorganic acids. Suitable organic acids include maleic,fumaric, benzoic, ascorbic, succinic, methanesulfonic, acetic,trifluoroacetic, oxalic, propionic, tartaric, salicylic, citric,gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic,glycolic, glutamic, and benzenesulfonic acids. Suitable inorganic acidsinclude hydrochloric, hydrobromic, sulfuric, phosphoric, and nitricacids. Base addition salts included those salts that form with thecarboxylate anion and include salts formed with organic and inorganiccations such as those chosen from the alkali and alkaline earth metals(for example, lithium, sodium, potassium, magnesium, barium andcalcium), as well as the ammonium ion and substituted derivativesthereof (for example, dibenzylammonium, benzylammonium,2-hydroxyethylammonium, and the like). Thus, the term “pharmaceuticallyacceptable salt” of structure (I) is intended to encompass any and allacceptable salt forms.

In addition, prodrugs are also included within the context of thisinvention. Prodrugs are any covalently bonded carriers that release acompound of structure (I) in vivo when such prodrug is administered to apatient. Prodrugs are generally prepared by modifying functional groupsin a way such that the modification is cleaved, either by routinemanipulation or in vivo, yielding the parent compound. Prodrugs include,for example, compounds of this invention wherein hydroxy, amine orsulfhydryl groups are bonded to any group that, when administered to apatient, cleaves to form the hydroxy, amine or sulfhydryl groups. Thus,representative examples of prodrugs include (but are not limited to)acetate, formate and benzoate derivatives of alcohol and aminefunctional groups of the compounds of structure (I). Further, in thecase of a carboxylic acid (—COOH), esters may be employed, such asmethyl esters, ethyl esters, and the like.

With regard to stereoisomers, the compounds of structure (I) may havechiral centers and may occur as racemates, racemic mixtures and asindividual enantiomers or diastereomers. Compounds of structure (I) mayalso possess axial chirality, which may result in atropisomers. All suchisomeric forms are included within the present invention, includingmixtures thereof. Furthermore, some of the crystalline forms of thecompounds of structure (I) may exist as polymorphs, which are includedin the present invention. In addition, some of the compounds ofstructure (I) may also form solvates with water or other organicsolvents. Such solvates are similarly included within the scope of thisinvention.

The effectiveness of a compound as a GnRH receptor antagonist may bedetermined by various assay methods. Suitable GnRH antagonists of thisinvention are capable of inhibiting the specific binding of GnRH to itsreceptor and antagonizing activities associated with GnRH. For example,inhibition of GnRH stimulated LH release in immature rats may bemeasured according to the method of Vilchez-Martinez (Endocrinology96:1130-1134, 1975). Briefly, twenty-five day old male Spraque-Dawleyrats are administered an GnRH antagonist in saline or other suitableformulation by oral gavage, sub-cutaneous injection, or intravenousinjection. This is followed by sub-cutaneous injection of 200 ng GnRH in0.2 ml saline. Thirty minutes after the last injection, the animals aredecapitated and trunk blood collected. After centrifugation, theseparated plasma is stored at −20° C. until determination of the LH andFSH by radioimmunoassay. Other techniques for determining the activityof GnRH receptor antagonists are well known in the field, such as theuse of cultured pituitary cells for measuring GnRH activity (Vale etal., Endocrinology 91:562-572, 1972), and a technique for measuringradioligand binding to rat pituitary membranes (Perrin et al., Mol.Pharmacol. 23:44-51, 1983).

For example, effectiveness of a compound as a GnRH receptor antagonistmay be determined by one or more of the following assays.

Rat Anterior Pituitary Cell Culture Assay of GnRH Antagonists

Anterior pituitary glands are collected from 7-week-old femaleSprague-Dawley rats and the harvested glands digested with collagenasein a dispersion flask for 1.5 hr at 37° C. After collagenase digestion,the glands are further digested with neuramimidase for 9 min at 37° C.The digested tissue is then washed with 0.1% BSA/McCoy's 5A medium, andthe washed cells suspended in 3% FBS/0.1 BSA/McCoy's SA medium andplated into 96-well tissue culture plates at a cell density of 40,000cells per well in 200 μl medium. The cells are then incubated at 37° C.for 3 days. One pituitary gland normally yields one 96-well plate ofcells, which can be used for assaying three compounds. For assay of anGnRH antagonist, the incubated cells are first washed with 0.1%BSA/McCoy's 5A medium once, followed by addition of the test sample plus1 nM GnRH in 200 μl 0.1% BSA/McCoy's 5A medium in triplicate wells. Eachsample is assayed at 5-dose levels to generate a dose-response curve fordetermination of its potency on the inhibition of GnRH stimulated LHand/or FSH release. After 4-hr incubation at 37° C., the medium isharvested and the level of LH and/or FSH secreted into the mediumdetermined by RIA.

RIA of LH and FSH

For determination of the LH levels, each sample medium is assayed induplicates and all dilutions are done with RIA buffer (0.01M sodiumphosphate buffer/0.15M NaCl/1% BSA/0.01% NaN3, pH 7.5) and the assay kitis obtained from the Nation Hormone and Pituitary Program supported byNIDDK. To a 12×75 mm polyethylene test tube is added 100 μl of samplemedium diluted 1:5 or rLH standard in RIA buffer and 100 μl of[125I]-labeled rLH (˜30,000 cpm) plus 100 μl of rabbit anti-rLH antibodydiluted 1:187,500 and 100 μl RIA buffer. The mixture is incubated atroom temperature over-night. In the next day, 100 μl of goat anti-rabbitIgG diluted 1:20 and 100 μl of normal rabbit serum diluted 1:1000 areadded and the mixture incubated for another 3 hr at room temperature.The incubated tubes are then centrifuged at 3,000 rpm for 30 min and thesupernatant removed by suction. The remaining pellet in the tubes iscounted in a gamma-counter. RIA of FSH is done in a similar fashion asthe assay for LH with substitution of the LH antibody by the FSHantibody diluted 1:30,000 and the labeled rLH by the labeled rFSH.

Radio-Iodination of GnRH Peptide

The GnRH analog is labeled by the chloramine-T method. To 10 μg ofpeptide in 20 μl of 0.5M sodium phosphate buffer, pH 7.6, is added 1 mCiof Na125I, followed by 22.5 μg chloramine-T and the mixture vortexed for20 sec. The reaction is stopped by the addition of 60 μg sodiummetabisulfite and the free iodine is removed by passing the iodinatedmixture through a C-8 Sep-Pak cartridge (Millipore Corp., Milford,Mass.). The peptide is eluted with a small volume of 80%acetonitrile/water. The recovered labeled peptide is further purified byreverse phase HPLC on a Vydac C-18 analytical column (The SeparationsGroup, Hesperia, Calif.) on a Beckman 334 gradient HPLC system using agradient of acetonitrile in 0.1% TFA. The purified radioactive peptideis stored in 0.1% BSA/20% acetonitrile/0.1% TFA at −80° C. and can beused for up to 4 weeks.

GnRH Receptor Membrane Binding Assay

Cells stably, or transiently, transfected with GnRH receptor expressionvectors are harvested, resuspended in 5% sucrose and homogenized using apolytron homogenizer (2×15 sec). Nucleii are removed by centrifugation(3000×g for 5 min.), and the supernatant centrifuged (20,000×g for 30min, 4° C.) to collect the membrane fraction. The final membranepreparation is resuspended in binding buffer (10 mM Hepes (pH 7.5), 150mM NaCl, and 0.1% BSA) and stored at −70° C. Binding reactions areperformed in a Millipore MultiScreen 96-well filtration plate assemblywith polyethylenimine coated GF/C membranes. The reaction is initiatedby adding membranes (40 ug protein in 130 ul binding buffer) to 50 ul of[¹²⁵I]-labeled GnRH peptide (˜100,000 cpm), and 20 ul of competitor atvarying concentrations. The reaction is terminated after 90 minutes byapplication of vacuum and washing (2×) with phosphate buffered saline.Bound radioactivity is measured using 96-well scintillation counting(Packard Topcount) or by removing the filters from the plate and directgamma counting. K_(i) values are calculated from competition bindingdata using non-linear least squares regression using the Prism softwarepackage (GraphPad Software).

Activity of GnRH receptor antagonists are typically calculated from theIC₅₀ as the concentration of a compound necessary to displace 50% of theradiolabeled ligand from the GnRH receptor, and is reported as a “K_(i)”value calculated by the following equation:$K_{i} = \frac{{IC}_{50}}{1 + {L/K_{D}}}$where L=radioligand and K_(D)=affinity of radioligand for receptor(Cheng and Prusoff; Biochem. Pharmacol. 22:3099, 1973). GnRH receptorantagonists of this invention have a K_(i) of 100 μM or less. In apreferred embodiment of this invention, the GnRH receptor antagonistshave a K_(i) of less than 10 μM, and more preferably less than 1 μM, andeven more preferably less than 0.1 μM (i.e., 100 nM).

As mentioned above, the GnRH receptor antagonists of this invention haveutility over a wide range of therapeutic applications, and may be usedto treat a variety of sex-hormone related conditions in both men andwomen, as well as mammals in general. For example, such conditionsinclude endometriosis, uterine fibroids, polycystic ovarian disease,hirsutism, precocious puberty, gonadal steroid-dependent neoplasia suchas cancers of the prostate, breast and ovary, gonadotrophe pituitaryadenomas, sleep apnea, irritable bowel syndrome, premenstrual syndrome,benign prostatic hypertrophy, contraception and infertility (e.g.,assisted reproductive therapy such as in vitro fertilization).

The compounds of this invention are also useful as an adjunct totreatment of growth hormone deficiency and short stature, and for thetreatment of systemic lupus erythematosis.

In addition, the compounds are useful in combination with androgens,estrogens, progesterones, and antiestrogens and antiprogestogens for thetreatment of endometriosis, fibroids, and in contraception, as well asin combination with an angiotensin-converting enzyme inhibitor, anangiotensin II-receptor antagonist, or a renin inhibitor for thetreatment of uterine fibroids. The compounds may also be used incombination with bisphosphonates and other agents for the treatmentand/or prevention of disturbances of calcium, phosphate and bonemetabolism, and in combination with estrogens, progesterones and/orandrogens for the prevention or treatment of bone loss or hypogonadalsymptoms such as hot flashes during therapy with a GnRH antagonist.

In another embodiment of the invention, pharmaceutical compositionscontaining one or more GnRH receptor antagonists are disclosed. For thepurposes of administration, the compounds of the present invention maybe formulated as pharmaceutical compositions. Pharmaceuticalcompositions of the present invention comprise a GNRH receptorantagonist of the present invention and a pharmaceutically acceptablecarrier and/or diluent. The GNRH receptor antagonist is present in thecomposition in an amount which is effective to treat a particulardisorder—that is, in an amount sufficient to achieve GnRH receptorantagonist activity, and preferably with acceptable toxicity to thepatient. Typically, the pharmaceutical compositions of the presentinvention may include a GnRH receptor antagonist in an amount from 0.1mg to 250 mg per dosage depending upon the route of administration, andmore typically from 1 mg to 60 mg. Appropriate concentrations anddosages can be readily determined by one skilled in the art.

Pharmaceutically acceptable carrier and/or diluents are familiar tothose skilled in the art. For compositions formulated as liquidsolutions, acceptable carriers and/or diluents include saline andsterile water, and may optionally include antioxidants, buffers,bacteriostats and other common additives. The compositions can also beformulated as pills, capsules, granules, or tablets which contain, inaddition to a GnRH receptor antagonist, diluents, dispersing and surfaceactive agents, binders, and lubricants. One skilled in this art mayfurther formulate the GnRH receptor antagonist in an appropriate manner,and in accordance with accepted practices, such as those disclosed inRemington's Pharmaceutical Sciences, Gennaro, Ed., Mack Publishing Co.,Easton, Pa. 1990.

In another embodiment, the present invention provides a method fortreating sex-hormone related conditions as discussed above. Such methodsinclude administering of a compound of the present invention to awarm-blooded animal in an amount sufficient to treat the condition. Inthis context, “treat” includes prophylactic administration. Such methodsinclude systemic administration of a GnRH receptor antagonist of thisinvention, preferably in the form of a pharmaceutical composition asdiscussed above. As used herein, systemic administration includes oraland parenteral methods of administration. For oral administration,suitable pharmaceutical compositions of GnRH receptor antagonistsinclude powders, granules, pills, tablets, and capsules as well asliquids, syrups, suspensions, and emulsions. These compositions may alsoinclude flavorants, preservatives, suspending, thickening andemulsifying agents, and other pharmaceutically acceptable additives. Forparental administration, the compounds of the present invention can beprepared in aqueous injection solutions which may contain, in additionto the GnRH receptor antagonist, buffers, antioxidants, bacteriostats,and other additives commonly employed in such solutions.

The following example is provided for purposes of illustration, notlimitation. In summary, the GnRH receptor antagonists of this inventionmay be assayed by the general methods disclosed above, while thefollowing Examples disclose the synthesis of representative compounds ofthis invention.

EXAMPLE 1 Synthesis of 1-(2,6-Diflourobenzyl)-2,6-Dimethyl-3-Bromo-5-Ethoxycarbonyl-4-Pyridone

Step 1 A Ethyl-3-(2,6-difluorobenzylamino)crotonate:

2,6-Difluorobenzylamine (5.00 g, 35.0 mmol) was added to trimethylorthoformate (88.0 mL) under N₂. The resulting solution was stirred atroom temperature for 20 minutes. Ethyl acetoacetate (4.5 mL, 35.0 mmol)was then added dropwise and the resulting mixture stirred for 24 hours(reaction progress monitored by LC/MS). The volatiles were removed undervacuum and the product solidified upon standing. Yield 7.88 g (30.9mmol, 88%). ¹H NMR (CDCl₃, 300 MHz): 8.86 (br, 1H), 7.30-7.21 (m, 1H),6.94-6.81 (m, 2H), 4.48 (s, 2H), 4.07 (q, J=6.9 Hz, 2H), 2.03 (s, 3H),1.23 (t, J=6.9 Hz, 3H); LRMS m/z 256.1 (M⁺+1).

Step 1B 1-(2,6-Difluorobenzyl)-2,6-dimethyl-3-ethoxycarbonyl-4-pyridone:

A mixture of ethyl-3-(2,6-difluorobenzylamino)crotonate (2.55 g, 10.0mmol) and 2,2,6-trimethyl-1,3-dioxin-4-one (1.85 g, 13.0 mmol) intoluene (100 mL) was heated at reflux for 3 hours. The reaction progresswas monitored by LC/MS. An additional aliquot of2,2,6-trimethyl-1,3-dioxin-4-one (2.0 mL) was added and the reactionmixture was refluxed for another 2 hours. LC/MS indicated completeconversion to product. The mixture was cooled down and the solvent wasremoved in vacuo. The solid residue was triturated with diethyl ether toyield the product as a tan solid (1.37 g, 4.3 mmol, 43%). ¹H NMR (CDCl₃,300 MHz): 7.40-7.30 (m, 1H), 7.00-6.91 (m, 2H), 6.30 (s, 1H), 5.20 (s,2H), 4.37 (q, J=6.9 Hz, 2H), 2.37 (s, 3H), 2.31 (s, 3H), 1.35 (t, J=6.9Hz, 3H); LRMS m/z 322.1 (M⁺+1).

Step 1C1-(2,6-Difluorobenzyl)-2,6-dimethyl-3-bromo-5-ethoxycarbonyl-4-pyridone:

1-(2,6-Difluorobenzyl)-2,6-dimethyl-3-ethoxycarbonyl-4-pyridone (2.43 g,7.6 mmol) was dissolved in glacial acetic acid (25 mL) and treated withbromine (490 μL, 9.5 mmol). The resulting mixture was stirred at roomtemperature for 8 hours and poured into ice/water. The product wasextracted with dichloromethane, and the extracts were washed with 10%aqueous NaHCO₃, 5% aqueous Na₂S₂O₃ and brine. The organics were driedover anhydrous MgSO₄, filtered and evaporated in vacuo. The residue wastriturated with diethyl ether to give the product as a white solid (1.32g, 3.3 mmol, 43%). ¹H NMR (CDCl₃, 300 MHz): 7.41-7.31 (m, 1H), 7.00-6.92(m, 2H), 5.31 (s, 2H), 4.37 (q, J=6.9 Hz, 2H), 2.66 (s, 3H), 2.37 (s,3H), 1.37 (t, J=6.9 Hz, 3H); LRMS m/z 400.1 (M⁺−1), 402.1 (M⁺+1).

EXAMPLE 2 Synthesis of1-(2,6-Difluorobenzyl)-2,6-Dimethyl-3-(2-Fluoro-3-Methoxyphenyl)-5-[2-(2-Pyridyl)ethylaminomethyl]-4-Pyridone

Step 2A1-(2,6-Difluorobenzyl)-2,6-dimethyl-3-(2-fluoro-3-methoxyphenyl)-5-ethoxycarbonyl-4-pyridone:

1-(2,6-Difluorobenzyl)-2,6-dimethyl-3-bromo-5-ethoxycarbonyl-4-pyridone(1.5 g, 3.7 mmol) was evacuated in a pressure vessel with2-fluoro-3-methoxyphenyl boronic acid (764 mg, 4.5 mmol) andtetrakis(triphenylphosphine) palladium (0) (428 mg, 370 μmol). A mixtureof benzene/ethanol/1,2-dimethoxyethane (74 ml in a 10/1/11 ratio) andbarium hydroxide (saturated aqueous, about 0.5M) was then added undervacuum, the vessel sealed under N₂, and the reaction stirred at 90° C.for twelve hours, protected from light. The organic layer wasconcentrated and purified using flash silica chromatography(EtOAc/hexanes-1/4 to MeOH/CH₂Cl₂-2/98), with the product eluting as thethird spot. The product was dried as an amber oil (1.12 g, 2.5 mmol,68%). ¹H NMR (CDCl₃, 300 MHz) δ 6.80-7.80 (m, 6H), 5.29 (s, 2H),4.37-4.33 (m, 2H), 3.87 (s, 3H), 3.38 (s, 3H), 2.26 (s, 3H), 1.35 (t,3H); LCMS=446 (MH⁺).

Step 2B1-(2,6-Difluorobenzyl)-2,6-dimethyl-3-(2-fluoro-3-methoxyphenyl)-5-formyl-4-pyridone:

Diisobutylaluminum hydride (3.75 mmol, 3.75 ml of a 1.0M solution inhexanes ) was added dropwise to a stirring solution of1-(2,6-difluorobenzyl)-2,6-dimethyl-3-(2-fluoro-3-methoxyphenyl)-3-bromo-5-ethoxycarbonyl-4-pyridone(1.12 g, 2.5 mmol) in THF/DCM (30 mL/ 12 mL), at −78° C. under N₂. Asuspension was formed at the end of the addition. After 1 hour, anadditional aliquot of DIBAL-H (2.5 mmol, 2.5 mL of a 1.0 M solution inhexanes) was added. The reaction was stirred for 1 hour at −78° C. MeOH(50 mL) was carefully added to quench any unreacted DIBAL-H. Thesolution was concentrated, then partitioned between EtOAc and 1 M HCl.The organic layer was concentrated and purified using flash silica gelchromatography (100% hexanes to EtOAc/hexanes 3/2). The fourth spotwhich eluted was evaporated to give product as a cream colored solid. ¹HNMR (CDCl₃, 300 MHz) δ 10.55 (s, 1H), 6.80-7.75 (m, 6H), 5.36 (s, 2H),3.90 (s, 3H), 2.79 (s, 3H), 2.27 (s, 3H); LCMS=402 (MH⁺).

Step 2C1-(2,6-Difluorobenzyl)-2,6-dimethyl-3-(2-fluoro-3-methoxyphenyl)-5-[2-(2-pyridyl)ethylamino-4-pyridone:

Sodium borohydride (30 mg, 794 μmol) was added to a pre-mixed solutionof1-(2,6-difluorobenzyl)-2,6-dimethyl-3-(2-fluoro-3-methoxybenzyl)-5-formyl-4-pyridone(20 mg, 50 μmol) and the amine (excess) in MeOH (1 mL). Upon addition ofthe reducing agent, the solution quickly turned dark with the evolutionof gas. Product formation was instantaneous. The crude solution wasconcentrated, taken up in acetonitrile, filtered and purified using aGilson Prep-HPLC system, with the product obtained as a TFA salt in 32%yield. ¹H NMR (CDCl₃, 300 MHz) δ 8.52 (d, 1H), 8.19 (t, 1H), 7.83 (d,1H), 7.62 (t, 1H), 7.36 (m, 1H), 7.10 (t, 1H), 6.95 (m, 3H), 6.72 (t,1H), 5.44 (s, 2H), 4.28 (s, 2H), 3.86 (s, 3H), 3.59 (m, 2H), 3.50 (m,2H), 2.54 (s, 3H), 2.31 (s, 3H); MS=508 (MH⁺).

The following compounds were synthesized according to above procedure.

TABLE 1

MS No. R₆ R₁ (MH⁺) 2-1 2-F-3-MeOPh 2-PyridylCH₂CH₂ 508 2-2 2-F-3-MeOPhPhCH₂ 493 2-3 2-F-3-MeOPh 2-MeOPhCH₂ 523 2-4 2-F-3-MeOPh 2-MePhCH₂ 5072-5 2-F-3-MeOPh 2-PyridylCH₂ 494 2-6 3-MeOPh 2-PyridylCH₂CH₂ 490 2-73-MeOPh PhCH₂ 475 2-8 3-MeOPh 2-MeOPhCH₂ 505 2-9 3-MeOPh 2-MePhCH₂ 4892-10 3-MeOPh

494 2-11 3-MeOPh

538 2-12 3-MeOPh Me₂NCH₂CH₂ 456 2-13 3-MeOPh (iPr)₂NCH₂CH₂ 512 2-143-MeOPh (HOCH₂CH₂)₂NCH₂CH₂ 516 2-15 3-MeOPh

544 2-16 3-MeOPh

586 2-17 3-MeOPh

481.2 2-18 3-MeOPh

465.1 2-19 3-MeOPh

570.3 2-20 3-MeOPh

501.2 2-21 3-MeOPh PhCH(CH₃) 489.2 2-22 3-MeOPh (CH₃)₃CCH(CH₃) 469.22-23 3-MeOPh F₃CCH₂ 467.1 2-24 3-MeOPh 2-MeO-PhCH₂CH₂ 519.2 2-25 3-MeOPh3,4-di-(OMe)PhCH₂CH₂ 549.2 2-26 3-MeOPh n-Heptyl 483.6 2-27 3-MeOPh3-NO₂PhCH₂ 520.5 2-28 3-MeOPh CyclopropylCH₂ 439.2 2-29 3-MeOPh4-ClPhCH(CH₃) 523.1 2-30 3-MeOPh Et 413.5 2-31 3-MeOPh Allyl 425.5 2-323-MeOPh Isopropyl 441.5 2-33 3-MeOPh 2-CF₃-4-Cl—PhCH₂ 561.2 2-34 3-MeOPh3,4-di-Cl—PhCH₂ 543.1 2-35 3-MeOPh 4-MeO-PhCH₂CH₂ 519.2 2-36 3-MeOPhn-Propyl 427.1 2-37 3-MeOPh n-Butyl 441.5 2-38 3-MeOPh3,4,5-tri-OMe—PhCH₂ 565.2 2-39 3-MeOPh CH₃CH₂OCH₂CH₂ 457.5 2-40 3-MeOPhCH₃OCH₂(CH₃CH₂)CH 471.5 2-41 2-F-3-MeOPh 4-CH₃-Cyclohexyl-CH₂ 499.2 2-422-F-3-MeOPh F₃CCH₂ 485.1 2-43 2-F-3-MeOPh ((CH₃)₂CH)₂NCH₂CH₂ 530.2 2-442-F-3-MeOPh Cyclopropyl-CH₂ 457.1 2-45 2-F-3-MeOPh 4-Cl—PhCH₂ 527.1 2-46Ph 4-CH₃-Cyclohexyl-CH₂ 451.2 2-47 Ph 2-FurylCH₂ 435.1 2-48 Ph

540.2 2-49 Ph

471.2 2-50 Ph PhCH(CH₃) 459.2 2-51 Ph (CH₃)₃CCH(CH₃) 439.2 2-52 PhCF₃CH₂ 437.1 2-53 Ph 3,4-di-OMe—PhCH₂CH₂ 519.2 2-54 Ph (iPr)₂NCH₂CH₂482.2 2-55 Ph 2-CF₃-4-F-PhCH₂ 531.2 2-56 Ph 2-F—PhCH₂CH₂ 477.2 2-57 Ph(S)-2-NaphthylCH(CH₃) 509.2 2-58 Ph 4-OMe-PhCH₂CH₂ 489.6 2-592-CH₃-Thienyl 2-FurylCH₂ 455.5 2-60 2-CH₃-Thienyl

560.6 2-61 2-CH₃-Thienyl

491.1 2-62 2-CH₃-Thienyl PhCH(CH₃) 479.1 2-63 2-CH₃-Thienyl(CH₃)₃CCH(CH₃) 459.2 2-64 2-CH₃-Thienyl CF₃CH₂ 457.5 2-65 2-CH₃-Thienyl3,4-di-OMe—PhCH₂CH₂ 539.7 2-66 2-CH₃-Thienyl 4-F—PhCH₂CH₂ 497.6 2-672-CH₃-Thienyl (CH₃)₂CHCH₂CH₂CH(CH₃) 473.6 2-68 2-CH₃-Thienyl(iPr)₂NCH₂CH₂ 502.7 2-69 2-CH₃-Thienyl 4-Cl—PhCH(CH₃) 514.1 2-702-CH₃-Thienyl 2-CF₃-4-F—PhCH₂ 551.6 2-71 2-CH₃-Thienyl 2-F—PhCH₂CH₂497.1 2-72 2-CH₃-Thienyl

549.2 2-73 2-CH₃-Thienyl PhCH₂ 465.1 2-74 2-CH₃-Thienyl 3,4-di-Cl—PhCH₂535 2-75 2-CH₃-Thienyl 4-MeO—PhCH₂CH₂ 509.2 2-76 2-CH₃-Thienyl n-Propyl417.1 2-77 2-CH₃-Thienyl n-Butyl 431.1 2-78 2-CH₃-Thienyl CH₃CH₂OCH₂CH₂447.6 2-79 2-CH₃-Thienyl CH₃OCH₂CH(CH₂CH₃) 461.6 2-80 2-CH₃-Thienyl2-PyridylCH₂CH₂ 480.6 2-81 Ph Propyl 397.5 2-82 Ph CH₃CH₂OCH₂CH₂ 427.52-83 Ph CH₃OCH₂CH(CH₂CH₃) 441.5 2-84 Ph 2-PyridylCH₂CH₂ 460.5 2-852-F-3-MeOPh 2-Pyridyl 480 2-86 2-F-3-MeOPh 3-Pyridyl 480 2-872-F-3-MeOPh 2-Pyridyl-6-Me 494 2-88 2-F-3-MeOPh 2-Pyridyl-5-Me 494 2-892-F-3-MeOPh 2-Pyridyl-3,5-diMe 508 2-90 2-F-3-MeOPh 2-Pyridyl-4-Cl 5142-91 2-F-3-MeOPh 2-Pyridyl-4-Me 494 2-92 2-F-3-MeOPh 2-Pyridyl-3-Me 4942-93 2-F-3-MeOPh

530 2-94 2-F-3-MeOPh

530 2-95 2-F-3-MeOPh 2-Pyridyl-5-F 498 2-96 2-F-3-MeOPh 2-Pyrimidyl-4-Me495 2-97 2-F-3-MeOPh 2-Pyrimidyl-4,6-diMe 509 2-98 2-F-3-MeOPh

567 2-99 2-F-3-MeOPh

470 2-100 2-F-3-MeOPh

516 2-101 2-F-3-MeOPh

519 2-102 2-F-3-MeOPh

547 2-103 2-F-3-MeOPh

530 2-104 2-F-3-MeOPh

494 2-105 2-F-3-MeOPh 2-ClPh 513 2-106 2-F-3-MeOPh 2-MePh 493 2-1072-F-3-MeOPh 3-ClPh 513 2-108 2-F-3-MeOPh 3-MeOPh 509 2-109 2-F-3-MeOPh4-MeOPh 509 2-110 2-F-3-MeOPh 4-MePh 493The following compounds were also synthesized according to the aboveprocedure.

TABLE 2

No. R₆ R₁R₂N MS (MH⁺) 2-111 2-F-3-MeOPh 1-Pyrrolidinyl 457.1 2-1122-F-3-MeOPh 2,6-Dimethylmorpholinyl 501.2 2-113 2-CH₃-Thienyl1-Pyrrolidinyl 429.5 2-114 2-CH₃-Thienyl 2,6-Dimethylmorpholinyl 473.22-115 Ph 1-Pyrrolidinyl 409.5

EXAMPLE 3 Synthesis of1-(2,6-Difluorobenzyl)-2,6-Dimethyl-3-(2-Fluoro-3-Methoxyphenyl)-5-[2-(2-Pyridyl)Ethylaminomethyl]-4-Pyridone

Step 3A1-(2,6-Difluorobenzyl)-2,6-dimethyl-3-(2-fluoro-3-methoxyphenyl)-5-[N-{2-(2-pyridyl)ethyl}-N-methylaminomethyl]-4-pyridone:

Sodium triacetoxyborohydride (30 mg, 142 μmol) was added to a stirringsolution of1-(2,6-difluorobenzyl)-2,6-dimethyl-3-(2-fluoro-3-methoxybenzyl)-5-formyl-4-pyridone(20 mg, 50 μmol) and 2-(2-methylaminoethyl)pyridine (0.14 mL, 985 μmol)in dichloromethane (1 mL). The solution stirred overnight at r.t., MeOH(0.5 mL) was added and the solution concentrated, taken up inacetonitrile, filtered and purified using a Gilson Prep-HPLC system togive the product as a TFA salt in 34% yield.

The following compounds are synthesized according to above procedure.

TABLE 3

No. R₆ R₁R₂N— MS (MH⁺) 3-1 2-F-3-MeOPh 2-PyCH₂CH₂NMe 522 3-2 2-F-3-MeOPhPhCH₂NMe 507 3-3 2-F-3-MeOPh 2-PyCH₂NMe 508 3-4 2-F-3-MeOPh 2-PyCH₂NEt522 3-5 2-F-3-MeOPh (2-PyCH₂)₂N 585 3-6 3-MeOPh 2-PyCH₂CH₂NMe 504 3-73-MeOPh PhCH₂NMe 489 3-8 2-F-3-MeOPh Et₂N 516.2 3-9 2-CH₃-ThienylPhCH₂NCH₃ 479.6 3-10 2-CH₃-Thienyl 2-PyCH₂CH₂NCH₃ 494.6 3-112-CH₃-Thienyl Et₂NCH₂CH₂NCH₃ 488.7 3-12 Ph PhCH₂NCH₃ 459.6 3-13 PhButylNCH₃ 425.5 3-14 Ph 2-PyCH₂CH₂NCH₃ 474.2 3-15 Ph Et₂NCH₂CH₂NCH₃468.6

EXAMPLE 4 Synthesis of1-(2,6-Difluorobenzyl)-2,6-Dimethyl-3-(2-Fluoro-3-Methoxyphenyl)-5-[4-Propylpiperazinylmethyl]-4-Pyridone

Step 4A1-(2,6-Difluorobenzyl)-2,6-dimethyl-3-(3-methoxyphenyl)-5-formyl-4-pyridone:

1-(2,6-Difluorobenzyl)-2,6-dimethyl-3-bromo-5-formyl-pyrid-4-one (1.36g, 3.8 mmol) stirred with 3-methoxyphenyl boronic acid (696 mg, 4.6mmol) and tetrakis(triphenylphosphine)palladium(0) (439 mg, 380 μmol) inbenzene/ethanol/DME (76 ml, 10/1/11) and barium hydroxide (30 mL, sat.,aq.) under N₂ at 90° C., protected from light over 8 hours. The organiclayer was then concentrated and purified using flash silicachromatography (ethyl acetate/hexane-1/9), giving the product as acream-colored solid (622 mg, 1.6 mmol, 42% yield). ¹H NMR (CDCl₃, 300MHz) δ 10.55 (s, 1H), 7.41-7.31 (m, 2H), 7.00-6.74 (m, 5H), 5.35 (s,2H), 3.81 (s, 3H), 2.79 (s, 3H), 2.25 (s, 3H); MS: 384 (MH⁺).

Step 4B1-(2,6-Difluorobenzyl)-2,6-dimethyl-3-(3-methoxyphenyl)-5-[piperazinylmethyl]-4-pyridone:

Sodium triacetoxyborohydride (2.75 g, 13 mmol) was added to a stirringsolution of1-(2,6-difluorobenzyl)-2,6-dimethyl-3-(3-methoxyphenyl)-5-formyl-4-pyridone(2.5 g, 6.5 mmol) and 1-boc-piperazine (1.33 g, 7.2 mmol) in CH₂Cl₂ (45mL) at r.t. The solution was quenched with 1M KOH (5 mL) and the organiclayer purified using flash silica chromatography (1% MeOH in CH₂Cl₂) togive the boc protected product as a dark brown oil. The resulting oilwas treated with trifluoroacetic acid (5 mL, 6.5 mmol) in CH₂Cl₂ (20 mL)for one hour at r.t. The crude solution was concentrated and purifiedusing flash silica chromatography (2% MeOH in CH₂Cl₂ and dried to givethe product as a white foam (1.9 g, 3.4 mmol, 52% yield). ¹H NMR (CDCl₃,300 MHz) δ 7.38-7.28 (m, 2H), 6.97-6.74 (m, 5H), 5.30 (s, 2, H), 3.80(s, 3H), 3.49 (s, 2H), 3.20-2.80 (m, 8H), 2.52 (m, 3H) 2.19 (s, 3H). MS:568 (MH⁺).

Step 4C1-(2,6-Difluorobenzyl)-2,6-dimethyl-3-(3-methoxyphenyl)-5-[4-(2-ethoxycarbonylcyclopropanemethyl)piperazinylmethyl]-4-pyridone:

Sodium triacetoxyborohydride (30 mg, 141 μmol) was added to a stirringsolution of1-(2,6-difluorobenzyl)-2,6-dimethyl-3-(3-methoxyphenyl)-5-[piperazinylmethyl]-4-pyridone(50 mg, 88 μmol) with ethyl-2-formyl-1-cyclopropane carboxylate (0.05mL, 669 μmol) in CH₂Cl₂ (1 mL). The mixture stirred at r.t. for fivehours before being filtered and purified using the Gilson Prep-HPLCsystem, giving the product as a TFA salt (13.4 mg, 19 μmol, 22% yield).¹H NMR (CDCl₃, 300 MHz) δ 7.40-7.32 (m, 2H), 7.00-6.69 (m, 5H), 5.42 (s,2H), 4.37 (s, 2H), 4.19-4.07 (m, 2H), 3.80 (s, 3H), 3.68-3.48 (m, 8H),3.00-2.88 (m, 1H), 2.58 (s, 3H), 2.28 (m, 3H), 1.67-1.54 (m, 3H),1.36-1.22 (m, 5H). MS: 580 (MH⁺).

TABLE 4

No. R MS (MH⁺) 4-1 H 454 4-2 EtOCO(cPr)CH₂ 580 4-3 5-MeFuranCH₂ 548 4-43,4-MeOPhCH₂ 604 4-5 1-NaphCH₂ 594 4-6 iBu 510 4-7 Pr 496 4-8 c-PrCH₂508

EXAMPLE 5 Synthesis of1-(2,6-Difluorobenzyl)-2,6-Dimethyl-3-(2-Fluoro-3-Methoxyphenyl)-5-[N-{2-(2-Pyridyl)Ethyl}-N-Methylaminomethyl]-4-Pyridone

Step 5A 1-(2,6-Difluorobenzyl)-2,6-dimethyl-3-bromo-5-formyl-4-pyridone:

DIBAL (5.3 mmol, 5.3 mL of a 1.0 M solution in hexanes) was addeddropwise via syringe to a stirred solution of1-(2,6-difluorobenzyl)-2,6-dimethyl-3-bromo-5-ethoxycarbonyl-4-pyridone(1.40 g, 3.5 mmol) in THF/DCM (60 mL/20 mL), at −78° C. under N₂. Asuspension was formed at the end of the addition. After 1 hour, anadditional aliquot of DIBAL (3.0 mmol, 3.0 mL of a 1.0 M solution inhexanes) was added. The reaction was deemed complete after 1 hour at−78° C. MeOH (5 mL) was carefully added to quench any unreacted DIBALand the mixture was partitioned between EtOAc and 1 M HCl. The organiclayer was separated and washed with brine, dried over anhydrous MgSO₄and filtered. Upon removal of the solvents in vacuum, the crude solidresidue was triturated with Et₂O. The product was obtained as a beigesolid (0.80 g, 2.25 mmol, 64%). ¹H NMR (CDCl₃, 300 MHz): 10.55 (s, 1H),7.40-7.33 (m, 1H), 7.00-6.93 (m, 2H), 5.38 (s, 2H), 2.78 (s, 3H), 2.69(s, 3H); LRMS m/z 356.0 (M⁺−1), 358.0 (M⁺+1).

Step 5B1-(2,6-Difluorobenzyl)-2,6-dimethyl-3-bromo-5-(2-methoxyethenyl)4-pyridone:

KHMDS (2.4 mmol, 4.8 mL of a 0.5 M solution in toluene) was addeddropwise to a vigorously stirred suspension of(methoxymethyl)triphenylphosphonium chloride (771 mg, 2.25 mmol) inanhydrous THF (8 mL), at −78° C. under N₂. The resulting orangesuspension was stirred at −78° C. for 45 min. Then, a solution of1-(2,6-difluorobenzyl)-2,6-dimethyl-3-bromo-5-formyl-4-pyridone (534 mg,1.50 mmol) in THF (8 mL) was added dropwise and the reaction was allowedto warm slowly to room temperature. After 1 h at room temperature, thereaction was quenched with an aqueous saturated solution of NaHCO₃. Theorganics were extracted with EtOAc (50 mL), the organic layer wasseparated, washed with H₂O and brine, dried over MgSO₄, filtered andevaporated under vacuum. The crude residue was utilized in the nextstep. LRMS m/z 384.0 (M⁺−1), 386.0 (M⁺+1).

Step 5C1-(2,6-Difluorobenzyl)-2,6-dimethyl-3-bromo-5-(carbonylmethyl)4-pyridone:

The crude product above was dissolved in THF/H₂O (20 mL, 1:1 v/v) and tothat solution TFA (5 mL) was added. The mixture was heated at reflux for19 h. After cooling down, the reaction was extracted with CH₂Cl₂ (50mL), washed with sat. NaHCO₃ and brine. After drying over MgSO₄, thesolvent was removed under vacuum and the residue was chromatographed onsilica-gel, eluting with EtOAc. The product was obtained as a paleyellow oil (431 mg, 1.16 mmol, 78% over 2 steps). ¹H NMR (CDCl₃, 300MHz) δ 9.56 (t, J=1.8 Hz, 1H), 7.38-7.33 (m, 1H), 6.98-6.93 (m, 2H),5.37 (s, 2H), 3.83 (d, J=1.8 Hz, 2H), 2.68 (s, 3H), 2.33 (s, 3H); LRMSm/z 247.1 [M⁺-(Br, CH₂CHO)], 370.0 (M⁺−1), 372.0 (M⁺+1).

Step 5D1-(2,6-Difluorobenzyl)-2,6-dimethyl-3-bromo-5-[N-{2-(2-pyridyl)ethyl}-N-methylaminomethyl]-4-pyridone:

(2-Methylaminoethyl)pyridine (680 mg, 5.00 mmol) was added to a stirredsolution of1-(2,6-difluorobenzyl)-2,6-dimethyl-3-bromo-5-(carbonylmethyl)4-pyridone(430 mg, 1.16 mmol) in CH₂Cl₂ (15 mL). After 30 min., NaBH(OAc)₃ (1.23g, 5.80 mmol) was added in small portions, and the resulting mixture wasstirred at room temperature for 1 h. The reaction mixture was dilutedwith H₂O (15 mL) and the organic layer was separated and washed withsat. NaHCO₃ and brine. The organics were dried over MgSO₄, filtered andconcentrated in vacuo. The crude was used in the next step without anyfurther purification. Crude yield 426 mg (75%). LRMS m/z 490.0 (M⁺−1),492.0 (M⁺+1).

Step 5E1-(2,6-Difluorobenzyl)-2,6-dimethyl-3-(2-fluoro-3-methoxyphenyl)-5-[N-{2-(2-pyridyl)ethyl}-N-methylaminomethyl]4-pyridone:

The above crude bromide (98 mg, 0.20 mmol) and 3-methoxyphenyl boronicacid (36 mg, 0.24 mmol) were dissolved in DME/benzene/EtOH (11:10:1, 5mL). To that, saturated aqueous Ba(OH)₂ (1.4 mL) was added and themixture was degassed under N₂ for 30 minutes. Pd[Ph₃P]₄ (23 mg, 0.02mmol) was then added and the sealed reaction vessel was stirred at 80°C. for 18 h. The reaction mixture was cooled down, extracted with EtOAc,washed with H₂O and brine, dried over MgSO₄, filtered and evaporated.The residue was purified by preparative TLC plate (0.5 mm, 20×20 cm),eluting with a CHCl₃/MeOH/NH₄OH (88.5:11.0:0.5) mixture to give product(15 mg, 0.03 mmol, 15% yield). ¹H NMR (CDCl₃, 300 MHz) δ 8.50 (d, J=4.2Hz, 1H), 7.57 (dt, J₁=1.8 Hz, J₂=7.5 Hz, 1H), 7.36-7.27 (m, 2H), 7.20(d, J=7.5 Hz, 1H), 7.11-7.07 (m, 1H), 6.97-6.92 (m, 2H), 6.86-6.73 (m,3H), 5.30 (s, 2H), 3.80 (s, 3H), 3.03-2.97 (m, 2H), 2.92-2.83 (m, 4H),2.62-2.56 (m, 2H), 2.44 (s, 3H), 2.40 (s, 3H), 2.21 (s, 3H); LRMS m/z518.3 (M⁺1).

The following compounds are synthesized according to above procedure.

TABLE 5

No. R₆ R₁R₂N MS (MH⁺) 5-1 2-F-3-MeOPh 2-PyCH₂CH₂NMe 536 5-2 3,4-CH₂O₂Ph2-PyCH₂CH₂NMe 532 5-3 4-iPrPh 2-PyCH₂CH₂NMe 530 5-4 3-MeOPh2-PyCH₂CH₂NMe 518

EXAMPLE 6 Synthesis of1-(2,6-Difluorobenzyl)-2-Methyl-3-[(2R)-Amino-2-Phenylethoxyl]-5-Arylpyridin-4-One

Step 6A 2-Methyl-3-[(2R)-Boc-amino-2-phenylethoxy]-4H-pyran-4-one:

Diethyl azodicarboxylate (2.36 mL, 15.0 mmol) was added dropwise to astirred solution of Maltol (1.26 g, 10.0 mmol), triphenylphosphine (3.93g, 15.0 mmol) and (R)-N-boc-phenylglycinol (2.37 g, 10.0 mmol) in THF(100 mL). The initial yellow color faded quickly, and the resultingcolorless solution was stirred under N₂ for 15 h at room temperature.The solvent was removed in vacuo and the residue was purified on silicagel, eluting with a 2:1 v/v mixture of hexanes/EtOAc. The title productwas obtained as a yellow oil, which was contaminated with sometriphenylphosphine oxide. This mixture was carried onto the next stepwithout any further purification. Yield=2.35 g. LRMS m/z 246 (M⁺−boc+1),229 (246—NH₃).

Step 6B1-(2,6-Difluorobenzyl)-2-methyl-3-[(2R)-Boc-amino-2-phenylethoxy]-pyridin-4-one:

Crude 2-methyl-3-[(2R)-Boc-amino-2-phenylethoxy]-4H-pyran-4-one (1.00 g,˜2.90 mmol), 2,6-difluorobenzyl amine (700 μL, 5.8 mmol) and ethanol (3mL) were combined and heated to 120° C. in a pressure vessel. After 16h, the volatiles were removed in vacuo and the residue purified bycolumn chromatography, eluting with EtOAc. The product was isolated as awhite foam (204 mg, 0.43 mmol, 15%, assuming pure starting material). ¹HNMR (CDCl₃-300 MHz) δ 7.42-7.19 (m, 7H); 6.98 (t, J=8.1 Hz, 2H); 6.43(d, J=7.8 Hz, 1H); 5.06 (s, 2H); 4.87-4.83 (m, 1H); 4.06 (dd, J₁=9.9 Hz,J₂=4.2 Hz, 1H); 3.93 (dd, J=9.9 Hz, J₂=6.8 Hz, 1H); 2.34 (s, 3H); 1.42(s, 9H); LRMS m/z 471.1 (M⁺+1), 371.0 (M⁺−boc+1).

Step 6C1-(2,6-Difluorobenzyl)-2-methyl-3-[(2R)-Boc-amino-2-phenylethoxy]-5-bromopyridin-4-one:

N-Bromosuccinimide (79 mg, 0.44 mmol) was added to a stirred solution of1-(2,6-difluorobenzyl)-2-methyl-3-[(2R)-Boc-amino-2-phenylethoxy]-5-bromopyridin-4-one(173 mg, 0.37 mmol) in THF (2 mL), under an atmosphere of N₂. Theresulting mixture was refluxed for 2 h and the mixture was cooled toroom temperature and partitioned between EtOAc and H₂O. The organiclayer was separated, washed with aqueous NaHCO₃ and brine, dried overanhydrous MgSO₄, filtered and concentrated in vacuo. The product wasobtained as a yellow foam (185 mg, 0.34 mmol, 92%). ¹H NMR (CDCl₃-300MHz) δ 7.76 (s, 1H); 7.47-7.19 (m, 6H); 7.00 (t, J=8.1 Hz, 2H); 5.09 (s,2H); 4.90-4.87 (m, 1H); 4.09-4.00 (m, 2H); 2.34 (s, 3H); 1.41 (s, 9H);LRMS m/z 551.1 (M⁺+3), 549.1 (M⁺+1), 451.0 (M⁺−boc+3), 449.0 (M⁺−boc+1).

Step 6D1-(2,6-Difluorobenzyl)-2-methyl-3-[(2R)-Boc-amino-2-phenylethoxy]-5-arylpyridin-4-one(General Procedure for Suzuki Couplings):

The aryl boronic acid (1.3 mmol) and aqueous saturated Ba(OH)₂ solution(7.1 mL) were added to a solution of1-(2,6-difluorobenzyl)-2-methyl-3-[(2R)-Boc-amino-2-phenylethoxy]-5-bromopyridin-4-one(1.0 mmol) in a solvent mixture consisting of dimethoxyethane, benzeneand ethanol, in a 50:45.5:4.5 ratio (20 mL), respectively. The resultingmixture was degassed by bubbling N₂ for about 20 minutes. Pd[PPh₃]₄ (0.1mmol) was then added, the vessel was sealed and immersed in an oil bathat 90° C., with stirring. The reaction was monitored by TLC and LC/MS.When the starting material was consumed (typically 5-10 hours), thereaction was cooled and partitioned between EtOAc and water. The organiclayer was washed with brine, dried over MgSO₄ and filtered. Thefiltrates were concentrated in vacuum and the residue was purified bycolumn chromatography on silica gel. Yields typically range from 65-95%.

Step 6E1-(2,6-Difluorobenzyl)-2-methyl-3-[(2R)-amino-2-phenylethoxy]-5-arylpyridin-4-one(General Procedure for N-boc Deprotections)

Trifluoroacetic acid (2 mL) was added to a solution of1-(2,6-difluorobenzyl)-2-methyl-3-[(2R)-Boc-amino-2-phenylethoxy]-5-arylpyridin-4-one(0.09 mmol) in CH₂Cl₂ (2 mL) and the resulting mixture was stirred atroom temperature for 2 h. TLC and LC/MS analysis showed that allstarting material had been consumed. The volatiles were removed in vacuoand the residues were either purified directly by preparative HPLC orneutralized with NH₃ in MeOH and then purified by preparative TLC,eluting with a 88:11:1 v/v mixture of CHCl₃/MeOH/NH₄OH.

TABLE 6

No. R₆ ¹H NMR(CDCl₃, 300MHz) MS (MH⁺) 6-1 3-MeOPh 7.55(s, 1H);7.44-7.22(m, 8H); 477 7.11(dd, J₁=1.0Hz, J₂=7.7Hz, 1H); 6.99(t, J=8.1Hz,2H); 6.86(dd, J₁=1.7Hz, J₂=8.3Hz, 1H); 5.12(s, 2H); 4.47-4.43(m, 1H);4.19(dd, J₁=4.1Hz, J₂=9.5Hz, 1H); 4.00(dd, J₁=9.0Hz, J₂=9.5Hz, 1H);3.83(s, 3H); 2.37(s, 3H) 6-2 3,4-CH₂O₂Ph 7.49(s, 1H); 7.44-7.22(m, 6H),491 7.16(d, J=1.8Hz, 1H), 7.01- 6.96(m, 3H); 6.83(d, J=8.1Hz, 1H);5.95(s, 2H); 5.11(s, 2H); 4.46- 4.42(m, 1H); 4.17(dd, J₁=4.0Hz,J₂=9.3Hz, 1H); 3.99(dd, J₁=8.7Hz, J₂=9.3Hz, 1H); 2.36(s, 3H) 6-32-F-3-MeOPh 495

EXAMPLE 7 Synthesis of1-(2,6-difluorobenzyl)-2,6-dimethyl-3-[N-(2-aminoethyl)aminomethyl]-5-(2-fluoro-3-methoxy)pyridin-4-one

Step 7A1-(2,6-Difluorobenzyl)-2,6-dimethyl-3-(2-fluoro-3-methoxyphenyl)-5-(2-aminoethyl)methylamino-4-pyridone

Butyl(tert)-N-(2-aminoethyl)carbamate (530 mg, 3.3 mmol) was added to astirring solution of1-(2,6-Difluorobenzyl)-2,6-dimethyl-3-(2-fluoro-3-methoxyphenyl)-5-formyl-4-pyridone(870 mg, 2.2 mmol) and magnesium sulfate (145 mg, 1.2 mmol) in methanol(29 mL) at room temperature. The resulting mixture stirred 1 hour beforeaddition of sodium borohydride (145 mg, 3.8 mmol). The crude reactionwas concentrated in vacuo and purified by Flash silica chromatography,and dried as an amber oil. Yield 460 mg (843 μmol, 38%). LCMS m/z 546(M⁺+1).

Trifluoroacetic acid (10 mL, 130 mmol) was added to the boc-protecteddiaminoethylpyridone (460 mg, 843 μmol) in dichloromethane (20 mL) andstirred for 8 h at r.t. The material was dried in vacuo as an oil, asTFA salt. Yield 470 mg (840 μmol, 99%). ¹H NMR (CDCl3, 300 MHz) δ7.37-7.29 (m, 1H), 7.13-7.09 (m, 1H), 6.97-6.92 (m, 3H), 6.83-6.79 (m,1H), 5.34 (s, 2H), 3.89 (s, 3H), 3.84 (s, 2H), 3.39 (m, 2H), 3.08 )(m,2H), 2.50 (s, 3H), 2.25 (s, 3H); LCMS m/z 446 (M⁺+1).

EXAMPLE 9 Synthesis of1-(2,6-difluorobenzyl)-2,6-dimethyl-3-[N-(2-phenyl-2-imidiazoline)methyl]-5-(2-fluror-3-methoxyphenyl)-4-pyridinone

Ethyl alcohol (1 mL, 17.7 mmol) was added to1-(2,6-difluorobenzyl)-2,6-dimethyl-3-[N-(2-aminoethyl)aminomethyl]-5-(2-fluoro-3-methoxy)-4-pyridoneTFA salt (95 mg, 170 μmol) with methyl benzimidate hydrochloride (35 mg,204 μmol), sealed in a glass pressure vessel and stirred for 2 h at 75°C. The crude material was purified using Prep-HPLC-MS, and dried invacuo as an oil (TFA salt). Yield 30.7 mg (48 μmol, 28%). ¹H NMR (CDCl3,300 MHz) δ 7.66-7.60 (m, 3H), 7.54-7.49 (m, 2H), 7.42-7.32 (m, 1H),7.14-7.08 (m, 1H), 7.03-6.93 (m, 3H), 6.70-6.65 (m, 1H), 5.44 (s, 2H),4.74 (s, 2H), 3.91 (m, 3H), 3.88 (m, 4H), 2.37 (s, 3H), 2.30 (s, 3H);LCMS m/z 532 (M⁺+1).

EXAMPLE 10 Synthesis of1-(2,6-difluorobenzyl)-2-methyl-3-[N-(quanyl)-N′-phenylaminomethyl]-5-(2-fluoro-3-methoxyphenyl)pyridin-4-one

N,N′-bis-boc-1-guanylpyrazole (195 mg, 627μmmol) was added to1-(2,6-difluorobenzyl)-2-methyl-3-(N-phenylaminomethyl)-5-(2-fluoro-3-methoxyphenyl)pyridin-4-one(150 mg, 313 μmmol) in 1,4-dioxane (6 mL), sealed in a glass pressurevessel and stirred for 8 h at 100° C. The crude material was purifiedusing Flash silica chromatography, and dried in vacuo as a clear oil.Yield 50 mg (69 umol, 22%).

Trifluoroacetic acid (2 mL, 26 mmol) was added to the boc-protectedguanylpyridone (50 mg, 69 μmol) in dichloromethane (5 mL) and stirredfor 2 h at r.t. The crude material was purified using Flash silicachromatography, and dried in vacuo as a clear yellow oil. Yield 2 mg(3.8 μmol, 5.5%). ¹H NMR (CDCl₃, 300 MHz) δ 7.30-7.20 (m, 4H), 7.05-6.82(m, 6H), 6.60-6.50 (m, 1H), 5.45 (s, 2H), 5.40-5.15 (m, 2H), 3.85 (s,3H), 2.40 (s, 3H), 2.15 (s, 3H); LCMS m/z 521 (M⁺+1).

It will be appreciated that, although specific embodiments of theinvention have been described herein for purposes of illustration,various modifications may be made without departing from the spirit andscope of the invention. Accordingly, the invention is not limited exceptas by the appended claims.

All of the above U.S. patents, U.S. patent application publications,U.S. patent applications, foreign patents, foreign patent applicationsand non-patent publications referred to int his specification and/orlisted in the Application Data Sheet are incorporated herein byreference, in their entirety.

1. A compound having the following structure:

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:A is O or a bond; n is 1, 2, 3 or 4; R₁ and R₂ are the same or differentand independently hydrogen, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, heterocycle, substitutedheterocycle, heterocyclealkyl, substituted heterocyclealkyl,—C(R₈)(═NR₉) or —C(NR₁₀R₁₁)(═NR₉); or R₁ and R₂ taken together with thenitrogen atom to which they are attached form a heterocycle or asubstituted heterocycle; R_(3a) and R_(3b) are the same or differentand, at each occurrence, independently hydrogen, alkyl, substitutedalkyl, alkoxy, alkylthio, alkylamino, aryl, substituted aryl, arylalkyl,substituted arylalkyl, heterocycle, substituted heterocycle,heterocyclealkyl, substituted heterocyclealkyl, —COOR₁₂ or —CONR₁₀R₁₁;or R_(3a) and R_(3b) taken together with the carbon atom to which theyare attached form a homocycle, substituted homocycle, heterocycle orsubstituted heterocycle; or R_(3a) and the carbon to which it isattached taken together with R₁ and the nitrogen to which it is attachedform a heterocycle or substituted heterocycle; R₄ is hydrogen, alkyl orsubstituted alkyl; R₅ is arylalkyl, substituted arylalkyl,heteroarylalkyl or substituted heteroarylalkyl; R₆ is aryl, substitutedaryl, heteroaryl or substituted heteroaryl; R₇ is hydrogen, alkyl orsubstituted alkyl; R₈, R₉, R₁₀ and R₁₁ are the same or different and, ateach occurrence, independently hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, heterocycle,substituted heterocycle, heterocyclealkyl or substitutedheterocyclealkyl; and R₁₂ is hydrogen, alkyl or substituted alkyl. 2.The compound of claim 1 wherein R₁ is hydrogen, alkyl, substitutedalkyl, arylalkyl, substituted arylalkyl, heterocyclealkyl or substitutedheterocyclealkyl.
 3. The compound of claim 1 wherein R₅ is arylalkyl,substituted arylalkyl or heteroarylalkyl.
 4. The compound of claim 1wherein R₆ is substituted aryl, heteroaryl or substituted heteroaryl. 5.A pharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier or diluent.